Myotonic dystrophy gene analysis in affected Israeli families

Myotonic dystrophy (DM) is an autosomal dominant disease with an estimated incidence of 1:7,500 individuals. The clinical manifestations are variable and include muscle wasting and weakness, myotonia, intellectual impairment, cardiac abnormalities, cataracts, and testicular atrophy. Despite its phenotypic variability, the disease is genetically homogeneous, and a specific molecular defect has been located to chromosome 19q13.3 and found to be associated with the expansion and instability of trinucleotide (CTG) repeats. Whereas normal individuals have 5-36 CTG repeats, affected individuals have 50 to several thousands. Therefore, DM can now be diagnosed accurately using molecular biology techniques that allow detailed analysis and determination of the size of DNA in the unstable DM gene region. In this way even mildly affected patients can be identified. We used this method to study the DM gene in 11 affected Israeli families (39 individuals). In most of the families, the unstable DNA sequence increased in size when transmitted to offspring. In one of the families we found contraction of the CTG repeat in a DM offspring of an affected male; and in another family a CTG repeat contraction occurred in three offspring of an affected female while in the fourth offspring there was CTG expansion. Southern blot analysis using BglI restriction provided the most accurate technical results. There was an obvious phenotype/genotype correlation between the size of the CTG repeat and severity of disease.